This, in all its molecular complexity, is the first scientifically accurate quantitative 3D model of a synapse. Even if it ‘only’ shows an average terminal without regard for the neurotransmitter it is still breathtaking how the 300,000 synaptic proteins fit into this tiny synaptic bouton and are still organized and fully functioning. This effort has been made possible only by an integrative approach. To create a 3D molecular model of the structure, researchers first isolated the synapses of rat neurons and used quantitative immunoblotting and mass spectrometry to identify and quantify the proteins present at every stage of the neurotransmitter release cycle. Then they turned to electron microscopy to determine organelle numbers, sizes and positions. Finally super-resolution fluorescence microscopy (STED) revealed the location of each protein.

The new findings reveal: copy numbers of proteins involved in the same step of synaptic vesicle recycling correlated closely and seemed to be tightly coordinated. In contrast copy numbers of proteins involved in different steps like exocytosis of synaptic vesicles (26,000 copies) and endocytosis of vesicles during recycling (1,000-4,000) differ over more than three orders of magnitude per synapse. Apparently, more than enough proteins are present to ensure vesicle release, but the proteins for vesicle recycling are sufficient for only 7-11% of all vesicles in the synapse. This means that the majority of vesicles in the synapse cannot be used simultaneously. The ultimate goal of the research team led by Prof. Rizzoli “is to reconstruct an entire nerve cell” to create in combination with functional studies a ‘virtual cell’.